We here propose a longitudinal, epidemiologic study of the genetic and environmental risk factors for major mood disorders, anxiety disorders, and alcohol dependence in male-male and male-female twin pairs from the population based Virginia Twin Registry. This study, which integrates two previously divergent traditions within psychiatric research, represents an extension of a highly successful study of female-female twin pairs from the same registry. Specifically, we propose to conduct two waves of assessment, at one year intervals, on both members of 2,800 twin pairs, of whom 1,500 will be male- male (around 55% monozygotic and 45% dizygotic) and 1,300 opposite-sex dizygotic twins. The first wave will be by phone and concentrate on major risk factors and symptom levels. The second wave will be in person and will assess risk factors, symptom levels and detailed one-year and lifetime prevalences for major depression, mania, generalized anxiety disorder, panic disorder, phobias, alcohol dependence and drug and alcohol abuse. Assessed environmental risk factors will include history of parental loss, parental rearing style, social class, personality, coping style, lifetime traumas, social support and stressful life events and difficulties. State-of-the-art sociometric and genetic analyses will produce advances in our understanding of the etiology of these conditions that have previously been beyond our grasp. We will be able to understand the etiologic role of genes and key environmental factors in these disorders in men, understand how genes and environment interact to produce illness, and clarify how these risk factors differentially impact on men and women. Insight will be gained into the role of genetic and environmental factors in the etiology of comorbidity. We will develop multivariate genetic models including specified environmental risk factors that will provide realistic etiologic models for these disorders that incorporate all major risk factor domains.